Young Jacob S, Cho Nam Woo, Lucas Calixto-Hope G, Najem Hinda, Mirchia Kanish, Chen William C, Seo Kyounghee, Zakimi Naomi, Daggubati Vikas, Casey-Clyde Tim, Nguyen Minh P, Chen Arya, Phillips Joanna J, Ozawa Tomoko, Aghi Manish K, Taylor Jennie W, DeRisi Joseph L, Bhaduri Aparna, Berger Mitchel S, Heimberger Amy B, Butowski Nicholas, Spitzer Matthew H, Raleigh David R
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
bioRxiv. 2025 Mar 14:2025.03.12.642800. doi: 10.1101/2025.03.12.642800.
The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to reveal that interleukin-6 (IL-6) inhibition reprograms the glioblastoma TIME to sensitize mouse glioblastoma to ICI and radiotherapy. Rare human glioblastoma patients who achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas who do not respond to ICI. Immune stimulatory gene therapy suppresses IL-6 tumor levels in preclinical murine models of glioblastoma. Furthermore, survival was longer in knockout mice with orthotopic SB28 glioblastoma relative to wild-type mice. IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma to anti-PD-1 by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and decreasing immunosuppressive Tregs. To translate these findings to a combination treatment strategy for recurrent glioblastoma patients, we show that IL-6 blockade plus ICI durably sensitizes mouse glioblastoma to high-dose radiotherapy.
胶质母细胞瘤肿瘤免疫微环境（TIME）是治疗的免疫抑制屏障，阻碍了胶质母细胞瘤对免疫检查点抑制（ICI）的反应。免疫抑制细胞因子、促肿瘤髓样细胞和耗竭的T细胞是胶质母细胞瘤TIME的特征。在这里，我们将ICI治疗前后患者匹配的人胶质母细胞瘤样本的空间和单细胞分析与临床前模型中的基因、免疫、单细胞和药理学研究相结合，以揭示白细胞介素-6（IL-6）抑制可重新编程胶质母细胞瘤TIME，使小鼠胶质母细胞瘤对ICI和放疗敏感。与对ICI无反应的胶质母细胞瘤相比，对ICI有临床反应的罕见人类胶质母细胞瘤患者治疗前IL-6水平较低。免疫刺激基因疗法可抑制胶质母细胞瘤临床前小鼠模型中的IL-6肿瘤水平。此外，原位接种SB28胶质母细胞瘤的基因敲除小鼠的生存期比野生型小鼠更长。用中和抗体阻断IL-6可通过增加MHCII+单核细胞、CD103+迁移树突状细胞（DC）、CD11b+传统DC和效应CD8+T细胞，并减少免疫抑制性调节性T细胞（Tregs），使小鼠胶质母细胞瘤对抗PD-1短暂敏感。为了将这些发现转化为复发性胶质母细胞瘤患者的联合治疗策略，我们表明，IL-6阻断加ICI可使小鼠胶质母细胞瘤对高剂量放疗持续敏感。
